[go: up one dir, main page]

EP2815754B1 - Compositions pour le traitement d' infections associeés à un film biologique - Google Patents

Compositions pour le traitement d' infections associeés à un film biologique Download PDF

Info

Publication number
EP2815754B1
EP2815754B1 EP14182618.0A EP14182618A EP2815754B1 EP 2815754 B1 EP2815754 B1 EP 2815754B1 EP 14182618 A EP14182618 A EP 14182618A EP 2815754 B1 EP2815754 B1 EP 2815754B1
Authority
EP
European Patent Office
Prior art keywords
wound
composition
biofilm
lactoferrin
xylitol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP14182618.0A
Other languages
German (de)
English (en)
Other versions
EP2815754A1 (fr
Inventor
Randall Wolcott
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glanbia Nutritionals Ireland Ltd
Original Assignee
Glanbia Nutritionals Ireland Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glanbia Nutritionals Ireland Ltd filed Critical Glanbia Nutritionals Ireland Ltd
Publication of EP2815754A1 publication Critical patent/EP2815754A1/fr
Application granted granted Critical
Publication of EP2815754B1 publication Critical patent/EP2815754B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/425—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0085—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the invention relates to compositions for promoting wound healing. More specifically, the invention relates to compositions for disrupting wound biofilm.
  • Chronic wounds are an increasingly more significant medical problem.
  • the severity of a medical problem is often reflected in the cost of providing care and, in the U.S. alone, the direct medical costs of chronic wound care are estimated to be several billion dollars. It is estimated that billions of dollars per year are spent on wound care products.
  • Venous leg ulcers affect millions of individuals and millions of individuals have decubitus ulcers.
  • Products include antimicrobials, such as compounds containing silver (cadexower iodine, methyline blue/gentian violet, nonspecific biocides (e.g. hydrogen peroxide, Dakin's solution, and vinegar); topical antibiotics; and moisturizing agents such as hydrocolloid gels, saline compositions (cellulose, alginate, etc.), and medium-chain dextrans (e.g., honey).
  • antimicrobials such as compounds containing silver (cadexower iodine, methyline blue/gentian violet, nonspecific biocides (e.g. hydrogen peroxide, Dakin's solution, and vinegar); topical antibiotics; and moisturizing agents such as hydrocolloid gels, saline compositions (cellulose, alginate, etc.), and medium-chain dextrans (e.g., honey).
  • Wound care products also include systemic and topical anti-infectives, injury management dressings and bandages, wound cleaners, debridement products, silver dressings, moist dressings such as alginates, films, foams, hydrocolloids and hydrogels, biological dressings such as artificial skin collagen and growth factors, and pressure relief products. More recently, biotechnology has contributed a variety of recombinant proteins, peptides, growth factors and other wound therapy products.
  • US2005/0053593A describes an antimicrobial composition
  • a lipid component and an enhancer component.
  • the enhancer component may comprise an organic acid, lactoferrin, and either a sugar, a sugar alcohol or both.
  • JP2001-181160A describes a swallowable dentifrice or oral cavity cleaning agent containing a mixture of lactoferrin, mucin and xylitol.
  • FR2822700A describes an ingestible buccal hygiene composition which comprises a gel matrix which retains active ingredients and releases them slowly into the mouth.
  • compositions for use in wound care comprise a therapeutically effective amount of a bovine milk-derived protein product ("MDPP") and xylitol.
  • MDPP comprises about 2 to about 200 mg per cc of the total composition and xylitol may comprise from at least about 2 to about 1000 mg per cc of the composition.
  • a composition may comprises any mammalian MDPP comprising at least about 2 % lactoferrin by weight, or a substantially pure isolated lactoferrin or a functional subunit or variant thereof, in combination with xylitol.
  • a composition may also comprise MDPP or isolated lactoferrin and xylitol in combination with a pharmaceutically acceptable carrier for topical application to a wound. At least one component of the pharmaceutically acceptable carrier may be a hydrocolloid gel.
  • compositions comprising non-human milk-derived apolactoferrin for topical application for the treatment of acute and chronic wounds.
  • Such compositions can comprise, for example, a milk-derived protein product having an iron content of about 0 % to about 20% (MDPP-A) optionally comprising at least one pharmaceutically acceptable carrier to facilitate topical administration of the MDPP-A.
  • the apolactoferrin may be an isolated lactoferrin of non-human mammalian origin or a variant thereof.
  • the MDPP-A may be combined with xylitol to provide a composition for treatment of acute and chronic wounds.
  • the method comprises applying to an acute or chronic wound a composition comprising MDPP, or isolated lactoferrin, and xylitol.
  • the method may also comprise applying to the wound at least one moisturizing agent such as, for example, methylcellulose/gelatin gel.
  • methods for treating chronic wounds by applying to a debrided wound a composition comprising an inhibitor of biofilm reconstitution (IBR) which, in various embodiments, may comprise lactoferrin and xylitol, MDPP and xylitol, MDPP, MDPP-A, or MDPP-A and xylitol.
  • IBR inhibitor of biofilm reconstitution
  • a method for inhibiting reconstitution of biofilm from biofilm fragments in a human or animal tissue comprising applying to the tissue a bovine milk-derived protein product processed to provide an enriched concentration of from about 2% to about 100% of the milk-derived protein product as lactoferrin and from about 0 to about 15 mg Fe/100g lactoferrin.
  • compositions comprising bovine milk-derived protein product (MDPP) provides a safe, highly-effective, and affordable topical wound care agent.
  • MDPP refers to a milk-derived fraction from a non-human mammal that contains an enriched concentration (i.e., greater than 2%) of lactoferrin.
  • Compositions of the present invention that the inventor has found to be especially effective for promoting wound healing comprise MDPP and xylitol.
  • Such compositions may also comprise isolated mammalian lactoferrin (including human lactoferrin), or subunits or variants thereof, in combination with xylitol.
  • Xylitol is a polyol, and a 5-carbon open chain sugar alcohol having the chemical name 1,2,3,4,5-Pentahydroxypentane. Pure xylitol is a white crystalline substance that looks and tastes like sugar. Natural sources of xylitol include, for example, plums, strawberries, and raspberries. While not being bound by theory, it is believed that the activity of xylitol may lie in its absence of reducing carbonyl groups. Therefore, non-reducing sugar alcohols such as, for example, sorbitol may also provide a benefit when used in a composition such as those described.
  • Lactoferrin is an iron-binding glycoprotein generally consisting of a single polypeptide chain with a molecular weight of 75,000 - 80,000 Daltons. LF can be isolated from a wide variety of dairy products and dairy- derived ingredients using industrial scale chromatography.
  • Compositions of the present invention may comprise a milk-derived protein product as described herein, but may also optionally utilize isolated or purified lactoferrin such as, for example, bovine milk-derived lactoferrin, other mammalian milk-derived lactoferrin, recombinant human lactoferrin, or variants of recombinant mammalian lactoferrin, in combination with xylitol to provide wound healing compositions. It is also within the scope of the invention to provide other non-human mammalian milk-derived protein products comprising at least about 2 to about 99 percent lactoferrin by weight in compositions for wound healing.
  • a chronic wound is defined herein as a wound that fails to progress through an orderly and timely sequence of repair or a wound that does not respond to treatment and/or the demands of treatment are beyond the patient's physical health, tolerance or stamina.
  • Those of skill in the art of wound care understand that many wounds that are, at first, considered to be acute wounds ultimately become chronic wounds due to factors still not well understood.
  • the inventor has determined that one very significant factor is the transition of planktonic bacteria within the wound to form a biofilm.
  • Biofilm disruption, or inhibition of biofilm reconstitution refers to the property demonstrated by the components of the present invention related to their ability to clear biofilm from a chronic or biofilm-containing acute wound or inhibit reconstitution of a biofilm mass from the remnants remaining after debridement and thereby promote healing of the wound.
  • the MDPP comprises at least about 10% bovine lactoferrin, which can have an iron content of from about 15mg/100g to about 40mg/100g. In other aspects, the MDPP may comprise at least about 50%, at least about 75%, or at least about 90% lactoferrin.
  • One form of a milk-derived protein product may also comprise the apolactoferrin form of lactoferrin, providing an iron concentration of from about Omg/100g to about 15mg/100g ("MDPP-A").
  • a composition comprising bovine MDPP or MDPP-A, or optionally an isolated mammalian lactoferrin protein such as bovine or human lactoferrin, or a variant thereof, in combination with xylitol is particularly effective for wounds that have been resistant to conventional wound-healing methods-wounds that might, under other circumstances, qualify an individual for amputation of the tissue surrounding the wound site.
  • aspects of the invention also provide compositions comprising MDPP or MDPP-A, xylitol, and at least one pharmaceutically acceptable carrier suitable for topical administration of the composition to the skin or to a wound surface.
  • Bioferrin ® 1000 (Glanbia Nutritionals, Inc., Monroe, Wisconsin) is a natural, biologically-active MDPP-A.
  • Bioferrin ® 2000 (Glanbia Nutritionals, Inc.) is a MDPP having higher iron content (15-40 mg/100g).
  • Xylitol may be obtained from a variety of commercial vendors such as, for example, Spectrum Chemicals and Laboratory Products, Gardena, California USA. Xylitol may also be isolated from natural sources including, for example, plums, strawberries, and raspberries.
  • Milk-derived protein isolates containing lactoferrin typically contain from about 15 to about 45 mg iron per 100 grams of protein isolate, but may also contain as much as 60 mg per grams of protein isolate.
  • the inventor has discovered that a milk-derived protein isolate processed to provide from about 0 to about 15 mg iron per 100 grams of protein isolate (i.e., lactoferrin is provided in the form of apolactoferrin) provides an especially effective wound healing agent when topically applied to the wound.
  • Bioferrin ® 1000 (Glanbia Nutritionals, Inc.) is a natural, biologically-active milk-derived protein product (MDPP-A) comprising bovine apolactoferrin from fresh sweet whey. It is isolated using fractionation separation techniques known to those of skill in the art and comprises greater than 90 percent protein, with greater than 90% of the total protein (e.g., 95%) comprising lactoferrin, primarily in the apolactoferrin form. Bioferrin® 1000 also has a moisture content of less than approximately 5 percent and less than approximately 2 percent ash.
  • MDPP-A biologically-active milk-derived protein product
  • Bioferrin® 1000 also has a moisture content of less than approximately 5 percent and less than approximately 2 percent ash.
  • a dry powder having a pH of greater than approximately 6.0 1% solution at 20° C
  • a wound-healing composition that may be applied as a powder, cream, gel, liquid, aerosol, or other topical preparation.
  • Slough which can be seen on the surface of a wound as in Fig. 1 , is comprised-predominantly of mixed-species bacterial biofilm, according to an analysis of wound slough samples performed for the inventor by the Center for Biofilm Engineering at Montana State University.
  • Chronic wounds have surprising similarities. At a biochemical level, chronic wounds display increased proinflammatory cytokines, increased matrix metalloproteases in a specific pattern, low levels of tissue inhibitors of matrix metalloproteases, low levels of growth factor cytokines along with degraded receptors on the cells constituting the wound bed (senescent cells).
  • the presence of biofilm which is ubiquitous in chronic wounds and a common characteristic of non-healing wounds, is consistent with each of the similarities found in chronic wounds. Biofilms demonstrate remarkable colony defenses against antibiotics, biocides, human immune system defenses, and most of the current wound care products used to treat chronic wounds today.
  • Biofilms isolated from any individual wound may comprise multiple different types of bacteria, both Gram positive and Gram negative. Whether among those with readily detectable biofilm or not, however, wounds are generally populated by a variety of bacterial species as well as fungal species. Furthermore, bacteria are more difficult to isolate and culture when present in the form of a biofilm, in part because they may be removed by swab or debridement as clusters of cells comprising multicellular matrix-enclosed biofilm fragments that do not form colonies when plated for identification and quantification. ( Costerton, W., et al. J. Clin. Invest. (2003) 112(10) 1466-1477 .)
  • study participants were chosen based upon the diagnosis of presence of non-infected wounds, the diagnosis having been made because of the lack of clinical signs of infection. Only 14.3% of those wounds in the control group and only 40.7% of wounds in the ultrasound treatment group were healed in 11-12 weeks, and investigators discovered that the "uninfected wounds" of more than 86% of the study participants contained greater than 100,000 colony-forming units of bacteria per gram of tissue. What was especially noteworthy was that the samples were cultured after debridement, suggesting that bacterial biofilm are not currently effectively identified as an inhibitor of healing, resulting in ineffective treatment and poor clinical outcomes (Ennis, W. et al (2005) 51(8): 24-39).
  • bovine lactoferrin although considered by some as a good antimicrobial, was not effective for wound healing.
  • the inventor has demonstrated that a bovine milk-derived protein product comprising lactoferrin is very effective for the treatment of acute and chronic wounds that would otherwise exhibit delayed healing due to the development of biofilm in the wound space and the difficulty usually experienced in clearing an established biofilm from a wound.
  • lactoferrin has demonstrated the ability to block initial biofilm formation by Pseudomonas in vitro
  • lactoferrin and iron depletion were actually demonstrated by Francesca et al. to stimulate biofilm formation by certain bacterial species, such as the Gram positive microorganism Streptococcus mutans.
  • Johnson et al. also demonstrated that Staphylococcus aureus biofilm production is induced in low-iron conditions and repressed by iron.
  • Even more puzzling have been studies indicating that elevated iron concentrations produced by application of various iron salts to bacterial cultures in 384-well plates ( Musk, D.
  • compositions of the present invention have demonstrated efficacy in vivo in a variety of human chronic/non-healing wounds in a significant number of patients.
  • Compositions in accordance with aspects of the present invention have demonstrated effectiveness in vivo in a clinical setting, and among the wounds healed as the result of treatment with these compositions have been many wounds formerly thought to be resistant to healing. For example, in multiple cases of diabetic foot ulcer where the composition has demonstrated effectiveness in healing a wound, the wound was serious enough to warrant classification as a Wagner's grade 4--an ulcer that has led to gangrene of the toes and/or forefoot.
  • biofilm is difficult, if not impossible, to remove in its entirety by standard debridement techniques, and biofilm tends to rebuild itself from remnants remaining in and around the wound space to return to or near its original volume, or reconstitute, quickly after debridement and standard therapy.
  • Agents effective at inhibiting biofilm reconstitution are especially effective at promoting healing in a wound that was previously considered to be "non-healing.”
  • a combination of milk-derived protein product preferably comprising at least about 10% bovine lactoferrin, in conjunction with xylitol, provides an effective and well-tolerated composition for inhibiting reconstitution of an established biofilm and promoting wound healing when applied topically to a wound.
  • MDPP milk-derived protein product
  • Bioferrin® 2000 Glanbia Nutritionals USA, Monroe, Wisconsin
  • compositions comprising MDPP (or, more preferably, MDPP-A), xylitol and at least one moisturizing agent, such as, for example, a hydrocolloid gel, a saline composition, a medium-chain dextran (e.g., honey), etc., for application to an acute or chronic wound.
  • moisturizing agent such as, for example, a hydrocolloid gel, a saline composition, a medium-chain dextran (e.g., honey), etc.
  • a suitable amount of MDPP Bioferrin®, Glanbia Nutritionals, Inc., Monroe, WI
  • Moisturizing agents suitable for wound care are known to those of skill in the art, and a number of such agents are commercially available.
  • compositions are provided comprising MDPP or MDPP-A, xylitol, and a silver product such as Acticoat ® (Smith and Nephew, Memphis, Tennessee).
  • compositions of the present invention may readily be used in conjunction with compositions and devices containing antimicrobial preparations of silver.
  • Acticoat ® may provide antimicrobial silver as a rayon/polyester non-woven core laminated between an upper and lower layer of silver-coated high density polyethylene (HDPE) mesh.
  • Acticoat ® Moisture Control (Smith and Nephew, Memphis, Tennessee) is a foam dressing comprising silver in nanocrystalline form.
  • Actisorb® Silver products distributed by Johnson and Johnson comprise activated charcoal cloth impregnated with silver (33 ⁇ g silver per square cm of cloth).
  • Arglaes ® products (Giltech Ltd., UK) also provide polymers for release of silver ions from a powder, film dressing, or other preparation for application to a wound.
  • compositions of the present invention may be incorporated into such products or used in combination with such products.
  • One advantage of augmenting the use of silver products with the use of compositions described by the invention is the ability to incorporate less silver into the products while achieving an improved effect on wound healing.
  • both compositions and devices are included, and may include woven or non-woven fabrics or polymers, alginates, foams, powders, gels, creams, liquids, wound fillers and other pharmaceuticals or medical devices deemed by those of skill in the art to be appropriate for effective delivery of silver compositions to a wound.
  • the composition is preferably applied following wound debridement.
  • biofilm bacteria cannot be completely eradicated from the wound area by debridement, decreasing biofilm mass and providing increased exposure of the debrided tissue and remaining biofilm bacteria to the inventive compositions increases wound healing.
  • the slough that fills a chronic wound previously thought to be comprised of dead cells, cellular debris, bacteria, and tissue fluid, has recently been demonstrated to be comprised primarily of a mixed-species bacterial biofilm. It is therefore of benefit to debride the slough from the wound as completely as possible.
  • Debridement can be performed by surgical, mechanical, autolytic, enzymatic, or a combination of means known to those of skill in the art of wound care.
  • gauze dressings to pack or cover the wound will preferably be avoided, since those dressings may enhance biofilm formation or reconstitution in the wound. If used, such dressings may, however, be coated or impregnated with a composition of the present invention to decrease the biofilm-enhancing properties of a gauze dressing.
  • One suggested course of treatment for example, comprises weekly debridement of a slough-containing wound and application of a composition as a fresh bandage is applied, which may be three times per week.
  • Topical wound care compositions may comprise about 2 to about 200 mg of MDPP or MDPP-A per cubic centimeter of total composition.
  • a composition comprises about 20 to about 200 mg of MDPP or MDPP-A, provided as Bioferrin ® 1000 or Bioferrin ® 2000, per cubic centimeter of total composition and about 1 to about 50, or in some embodiments about 5 to about 20, percent (w/v) xylitol.
  • this composition may be admixed into a methylcellulose/gelatin gel. This composition can be applied, in an amount of about 1 ⁇ 2 to about 5 cc of protein isolate/xylitol composition to each one square centimeter of wound area, to a freshly debrided chronic wound after the slough has been removed.
  • compositions of the invention may also comprise powders, solutions, ointments, aerosol sprays, and/or creams.
  • a wet-to-dry dressing e.g., gauze wetted with normal saline
  • a wet-to-dry dressing has been the standard dressing used by up to 80% of the physicians in the United States. Studies have shown that using this type of dressing results in healing in about 40-45% of wounds. Some use more recently-developed dressings of hydrogel and a semi-permeable primary dressing, and this has resulted in an increase in the percentage of wound healing to about 70%.
  • the inventive compositions and methods have been applied to hundreds of wounds to achieve minimally an 85% to 90% rate of wound healing in chronic wounds. The compositions and methods have also demonstrated efficacy in healing wounds that often would, under other circumstances, qualify a patient for amputation of the affected area.
  • compositions have demonstrated efficacy in protecting skin tears and other acute wounds in elderly patients in nursing homes from advancing to more serious wounds. These patients tend to be immunocompromised and more likely to develop chronic wounds. They also live in an environment in which they are more likely to be exposed to a variety of bacteria, often already in the biofilm state, and their acute wounds may quickly progress to the biofilm-infected chronic state. Therefore, compositions are provided comprising MDPP and/or MDPP-A, as well as compositions comprising MDPP and/or MPDI-A and xylitol, for the treatment of acute wounds such as, for example, cuts, cuts, scrapes, and tears of the skin.
  • compositions have been effectively used with nursing home patients who frequently experience skin tears, where they have been observed to decrease the frequency of transition from acute skin wound to Chronic wound.
  • Compositions may be applied topically to a wound as powders, aerosols, creams, gels, or other topical preparations or they may be applied to a bandage prior to application of the bandage to the wound.
  • Bandage surfaces may be coated with compositions of the invention, or the bandaging material may be impregnated with compositions of the invention.
  • an inventive wound care composition can promote healing of the types of wounds that would previously have been the basis for a decision to amputate the limb on which the wound was located.
  • Methods for treating chronic wounds comprising applying to a chronic wound a composition comprising an agent that disrupts biofilm reconstitution or reattachment.
  • Biofilm formation plays a key role in the transition from acute wound to chronic wound, and currently used antibiotic regimens, biocides, dressings, etc. are significantly less effective because of the presence of biofilm in the wound space.
  • application of a composition comprising an agent that disrupts biofilm reconstitution in certain aspects in combination with a moisturizing agent, promotes wound healing in a manner that significantly increases the percentage of healing in chronic, previously non-healing wounds.
  • Biofilm reconstitution can generally be detected by the reformation of slough in the wound space, and this slough is significantly reduced or eliminated as a result of treatment with compositions of the invention.
  • compositions of the invention may be applied without first debriding the wound.
  • compositions comprising MDPP, MDPP-A, lactoferrin, MDPP/xylitol, MDPP-A/xylitol, or lactoferrin/xylitol and at least one moisturizing agent, such as, for example, a hydrocolloid gel, a saline composition, a medium-chain dextran ( e.g., honey), etc., are provided for application to a chronic wound to inhibit biofilm reconstitution following debridement.
  • a moisturizing agent is an agent that promotes retention of water in the wound bed, such as an occlusive dressing, or is an agent that can donate water to the wound bed, such as a hydrogel.
  • compositions such as DuoDerm® Hydroactive Dressings (Bristol-Myers Squibb, Princeton, NJ), for example, can be used as a base into which a suitable amount of MDPP or MDPP-A (e.g. Bioferrin®1000 or Bioferrin®2000, Glanbia Nutritionals, Inc., Monroe, WI) is admixed.
  • MDPP or MDPP-A e.g. Bioferrin®1000 or Bioferrin®2000, Glanbia Nutritionals, Inc., Monroe, WI
  • Moisturizing agents suitable for wound care are known to those of skill in the art, and a number of such agents are commercially available.
  • the composition is applied following wound debridement.
  • biofilm is present in a variety of wounds, that it forms quickly in the wound space, and that it is primarily responsible for the chronic, non-healing nature of wounds commonly referred to as “chronic” wounds, as well as increased time to healing for "non-chronic” wounds.
  • chronic chronic, non-healing nature of wounds commonly referred to as "chronic” wounds
  • Much study has been done in the area of inhibiting biofilm formation on a surface, but by the time most patients present to a clinic or hospital, or by the time they realize themselves that a wound is serious enough to warrant the application of topical agents to improve healing, biofilm has already formed in the wound space.
  • This biofilm consists of cells of altered phenotype as compared to the planktonic cells from which they formed. Therefore, the inventor has focused his attention on identifying agents that act as inhibitors of biofilm reconstitution-those agents that disrupt biofilm or inhibit it from reforming from the remnants that remain in the wound area after debridement.
  • bovine milk protein products comprising at least about 2% lactoferrin by weight are effective agents for disrupting biofilm reformation or reconstitution.
  • a particularly effective composition for this purpose is a composition comprising a combination of lactoferrin and xylitol, optionally comprising a moisturizing agent that may be used to form a base for the composition.
  • the composition may be admixed into a methylcellulose gelatin gel. This composition can be applied in an amount of about 1A to about 5 cc of lactoferrin/xylitol composition to each one square centimeter of wound area to a freshly debrided chronic wound after the slough (biofilm) has been removed.
  • a composition may also be applied to a wound by use of a hydrophilic superabsorbent wound dressing, such as that described in United States Patent number 6,399,092 (Hobson, et al. 2002 ).
  • a preparation using hydrophilic dextran polymer beads may also be used for wound treatment, the preparation comprising hydrophilic dextran polymer beads and MDPP, MDPP-A, lactoferrin and xylitol, MDPP and xylitol, MDPP-A and xylitol, or combinations thereof.
  • Preparation of cross-linked beads for releasing an active agent into the wound while absorbing wound exudate are described in U.S. Patent Number 4,783,448 (Johansson, 1988 ).
  • compositions of the invention may also be applied to wound dressings, bandages, wound fillers, and other agents used for wound care to deliver the active agents to the wound or to provide additional benefit by making the bandage, filler, or other material less conducive to the development of a biofilm on the wound care dressing or bandage.
  • Compositions may be combined with, and/or applied to, a variety of different types of wound care products, including but not limited to hydrogel sheets, hydrogel wound fillers, absorptive dressings, alginates, compression dressings and wraps, composite dressings, and transparent films.
  • a wound care composition comprising MDPP, MDPP-A, lactoferrin, lactoferrin/xylitol, MDPP/xylitol, MDPP-A/xylitol, or combinations thereof lies in the safety of these ingredients if consumed.
  • Wound care products especially when applied to the surface of a large wound, may be absorbed by the tissue and distributed throughout the body. This can be a concern if components of the wound care products, such as iodine or silver nitrate, may have toxic effects if absorbed to a significant degree.
  • Milk-derived lactoferrin is generally recognized as safe at levels of consumption of 100 mg/product serving or 1.0 g/person/day (U.S. Food & Drug Administration, GRN000077 and GRN0000130).
  • compositions can be used for any chronic wound, including, for example, diabetic foot ulcers, decubitus ulcers, venous leg ulcers, and postoperative surgical wounds.
  • the compositions may also be used for biofilm-based infections which are accessible for application of MDPP, MDPP-A, MDPP/xylitol, MDPP-A/xylitol, or lactoferrin and xylitol, and which are likely to comprise mixed populations of bacterial species.
  • infections include, for example, sinus infections, rectal infections, oral lesions, intestinal conditions associated with biofilm or increased ( i.e., augmented) biofilm formation, and infections associated with indwelling devices such as catheters.
  • Acne vulgaris is a common skin disorder that affects a significant percentage of the population, especially during adolescence. It is often associated with the bacterium Propionibacterium acnes, and has been associated with biofilm formation.
  • Compositions in accordance with embodiments of the present invention provide a benefit for topical application for the treatment of such a biofilm-associated condition, particularly when provided in association with standard therapies such as systemic antibiotic treatment.
  • Substances such as pluronic lecithin organogels (PLOs) may be used to provide the moisturizing base and promote absorption of the active agents into the skin.
  • PLOs pluronic lecithin organogels
  • Augmented biofilm is generally an increased presence of biofilm or the presence of a significant number of bacteria in a biofilm that promote the disease state.
  • CHF chronic heart failure
  • compositions of the present invention are effective for inhibiting biofilm reconstitution and the fact that the intestine may be treated with oral therapeutics such as syrups, liquids, lozenges, tablets, caplets, etc.
  • the invention may provide compositions of treating biofilm-related or augmented biofilm-related conditions such as CHF by decreasing the augmented biofilm lining the intestine.
  • compositions may also comprise additional ingredients, provided that they do not chemically interact with, or otherwise interfere with the action of, the active ingredients of the composition.
  • Such ingredients can comprise, for example, additional moisturizing agents, gelling agents, lotion, cream, or other bases, antibiotic compositions, antifungal compositions, compositions for providing localized or systemic pain relief, etc.
  • a composition could comprise MDPP and/or MDPP-A and xylitol in combination with one or more antibiotics in a moisturizing gel base.
  • Compositions may also comprise, for example, growth factors such as platelet-derived growth factor, farnesol, furanone derivatives, and other agents that have been suggested for wound care.
  • Compositions may additionally include agents that have demonstrated effect in inhibiting biofilm formation, since some of those agents may also demonstrate inhibition of biofilm reconstitution.
  • Biofilms most often comprise a mixed population of bacteria, with Staphylococcus aureus , coliform bacteria, Bacteroides spp., Peptostreptococcus, Pseudomonas aeruginosa, Enterococcus pp., and Streptococcus pyogenes having been isolated from a diverse group of chronic wounds.
  • Antibiotic administration has been associated with the development of biofilms, and biofilms are characteristically resistant to antibiotic therapy. Even such agents as sodium hypochlorite, applied at full strength to an established biofilm, may kill only 50% of the biofilm.
  • composition aids in blocking reconstitution of the biofilm resident in the wound and may kill planktonic bacteria not yet established within the biofilm, particularly if one or more components of such a composition comprises at least one antibiotic.
  • This type of composition may also be administered to treat an acute wound, such as a newly-formed diabetic ulcer, to promote healing and prevent the wound from establishing biofilm and becoming a chronic wound.
  • compositions may be used for human wound therapy or for veterinary use.
  • Compositions may be applied topically to one or more wounds of, for example, a dog, cat, or other mammal.
  • Compositions may also be applied to a bite wound to protect a human from developing an ulcerated wound as the result of infection (often with biofilm fragments from the mouth of the animal).
  • Compositions may also include additional anti-plaque or anti-biofilm agents.
  • Lactoferrin combined with RNAIII inhibitory peptide (RIP) can have a synergistic effect and improves healing of chronic wounds.
  • RIP has been described in United States Patent Number 6,291,431 (Balaban, et al. ) .
  • the Southwestern Regional Wound Care Center (Lubbock, Texas) provided 50 samples from patients with chronic wounds. In addition, 15 patients with acute wounds less than 24 hours in duration were biopsied and their wound beds examined. The wound samples were evaluated using Gram staining and scanning electron microscopy.
  • Examples 2-11 patients' wounds were treated with an anti-biofilm agent comprising bovine lactoferrin (as Bioferrin® 1000 or Bioferrin® 2000 from Glanbia Nutritionals, Inc., Monroe, Wisconsin) at 20-mg/cc concentrations.
  • bovine lactoferrin as Bioferrin® 1000 or Bioferrin® 2000 from Glanbia Nutritionals, Inc., Monroe, Wisconsin
  • Xylitol one-, two-, three-, four-, and five-xypentane hydro from Spectrum Chemical
  • the base gel of the composition comprised methylcellulose (.023 gm/cc), gelatin (.013 gm/cc) and sterile water.
  • a 62-year-old diabetic white male had developed severe peripheral neuropathy and peripheral vascular disease. He presented with the wound necrosis of his left great toe pictured in Fig. 1 a with the infection tracking down the flexor tendon of his foot into the heel. He had very poor vascular status. This qualifies as a Wagner's V classification diabetic foot ulcer. The patient was very malnourished and had very difficult to manage diabetes, with blood glucose out of control (over 400) during the first 12 weeks of management.
  • the initial dressing changes comprised lactoferrin and a commercially available gel (Curasol® Hydrogel Wound Dressing, Healthpoint, Ltd.) along with Acticoat® (Smith & Nephew Wound Care, Hull, UK) .
  • the wound had begun with trauma, and infection was established in the great toe.
  • Wound care including IV antibiotics, local debridement, anti-biofilm agents and specific biocides to manage the surface, had been instituted to stop the spread of infection. Wound care was performed on a daily basis, yet the wound died back into the mid portion of the foot, as shown in Fig. 2a .
  • Lactoferrin therapy was instituted and the patient responded fairly quickly. Within several weeks, the progressive necrosis of the wound abated. The wound bed became granular with texture and color consistent with that of a healing wound. The drainage, pain and swelling in the left foot resolved. Seven months later the patient had complete healing of his wound, as shown in Fig. 2b . He was able to return to full activities including ambulation.
  • the patient was started on Bioferrin ® therapy after the sutures were out and there were 2 or 3 surface debridements. The patient responded very well to Bioferrin ® therapy. The drainage quickly reduced, the pain decreased and there was less swelling in the foot. The patient was continued on IV antibiotics, topical lactoferrin, specific biocides alternating between silver and Hydrofera Blue ® Hydrofera, LLC, Willimantic, CT) and moist interactive dressings to maintain the appropriate moisture of the surface. Within about five months, the wound had completely healed and the patient was ambulatory on the foot, returning to normal activity.
  • His primary dressings were mainly Biatain ® (Colplast A/S, Ltd., Humlebaek, Denmark) foam, with PolyMem ® (Ferris Corp., Burr Ridge, IL) used occasionally to control the moisture at an appropriate level. Over the next 5 weeks all wounds on his left lower extremity completely healed, and there has since been no regression. In this particular case, after 1 week of lactoferrin therapy the patient's wounds were very clean, with no evidence of slough (biofilm) on any of the wounds. The exudate dramatically decreased, the pain decreased, and the swelling involving his entire leg dramatically reduced over the first 2 weeks of therapy. As shown in Fig. 5b , after about six weeks, the patient's wounds were almost completely healed. He was able to return to his job and the level of function he enjoyed prior to the exacerbation.
  • the large chronic wound seen in Fig. 6a on the right thigh of this patient exhibited characteristics of significant biofilm formation, as seen by the appearance of the slough in Fig. 6a .
  • the wound was treated with a lactoferrin/xylitol composition of the present invention, admixed with Aquaphor® (Smith and Nephew Wound Care, Hull, UK).
  • Aquaphor® Smith and Nephew Wound Care, Hull, UK
  • the wound progressed rapidly to closure, although the patient was among those having multiple risk factors for chronic wound establishment-diabetes mellitus, peripheral vascular disease, malnutrition and renal failure on dialysis.
  • a 60-year-old female presented with a deep venous leg ulcer in early March.
  • the wound exhibited signs of significant biofilm incorporation.
  • the patient had no significant comorbidities.
  • the wound responded well to a composition comprising Bioferrin ® 1000 and moved to closure within 8 weeks.
  • the wound bed exhibited extensive fibrosis.
  • the wound was debrided aggressively on a weekly basis, and a composition comprising Bioferrin ® 1000/xylitol gel was applied to the wound.
  • the wound progressed to healing, despite the patient's severe venous insufficiency.
  • a very pleasant 84-year-old white female presented with a large non-healing surgical wound of her chest. She had undergone aortocoronary bypass grafting with total dehiscence of her chest wound. A vacuum assisted closure had been present for almost 2 months before she presented to the Wound Care Center.
  • the wound contained significant necrotic material at the base with 100% slough over the base. The base of the wound was irregular and there was copious drainage and a lot of erythema.
  • Bioferrin ® 2000 lactoferrin from milk-derived protein
  • the treatment was changed to Bioferrin ® 1000 with xylitol approximately 5 weeks after Bioferrin ® 2000 therapy had been initiated. After about 2 1 ⁇ 2 weeks of treatment with this composition, the wound exhibited good contraction, less necrotic material, an active edge around the wound, and was clearly healing. Within 3 months, there was a beefy red wound base, and the wound was healed a month later. The wound improved significantly when Bioferrin ® 1000 was introduced. The patient tolerated the treatments very well and experienced rapid closure of a very significant wound.
  • a 43-year-old male was kicked by a bull in the right lower leg, shattering his tibia and fibula and causing a compartment syndrome.
  • a metal plate was placed on the proximal fibula.
  • the patient was placed on Cubicin ® 6mg/kg with frequent irrigations and debridement of the wound and Hydrofera Blue ® was packed into the wound. After minimal progress, the wound appeared to be non-healing.
  • the presence of the metal plate and screw made the wound more difficult to heal, the device providing an environment for biofilm growth.
  • Bioferrin ® 1000 and xylitol was injected into the hole down the middle of the screw as an attempt to avoid hardware removal.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Materials For Medical Uses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (10)

  1. Composition comprenant une combinaison d'un produit protéique dérivé du lait contenant au moins 2 pour cent en poids de lactoferrine et du xylitol pour une utilisation dans le traitement d'infections sinusales et d'infections rectales qui ont pour origine un biofilm, d'infections associées à des dispositifs à demeure tels que des cathéters et d'affections intestinales liées à la formation d'un biofilm ou à son expansion (c.-à-d. à son accroissement).
  2. Composition pour l'utilisation selon la revendication 1, dans laquelle la quantité de produit protéique dérivé du lait va d'environ 2 mg à environ 200 mg par cc de la composition.
  3. Composition pour l'utilisation selon la revendication 1, dans laquelle le produit protéique dérivé du lait est un produit protéique dérivé du lait de bovins.
  4. Composition pour l'utilisation selon la revendication 1, dans laquelle le xylitol représente d'environ 1 pour cent (p/v) à environ 50 pour cent (p/v) de la composition.
  5. Composition pour l'utilisation selon la revendication 1, dans laquelle le xylitol représente d'environ 5 pour cent (p/v) à environ 20 pour cent (p/v) de la composition.
  6. Composition pour l'utilisation selon la revendication 1, qui comprend également un véhicule pharmaceutiquement acceptable.
  7. Composition pour l'utilisation selon la revendication 1, dans laquelle le véhicule pharmaceutiquement acceptable est sélectionné dans le groupe consistant en des mousses, alginates, hydrocolloïdes, produits de remplissage des plaies, hydrogels et films.
  8. Composition pour l'utilisation selon la revendication 1, qui comprend également de l'argent.
  9. Composition pour l'utilisation selon la revendication 1, dans laquelle la lactoferrine comprend d'environ 0 à environ 15 mg de Fe/100 g de lactoferrine.
  10. Composition pour l'utilisation selon la revendication 1, dans laquelle la lactoferrine comprend d'environ 15 à environ 40 mg de Fe/100 g de lactoferrine.
EP14182618.0A 2005-11-18 2006-11-18 Compositions pour le traitement d' infections associeés à un film biologique Not-in-force EP2815754B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US73839505P 2005-11-18 2005-11-18
US80569906P 2006-06-23 2006-06-23
EP06838046.8A EP1968627B1 (fr) 2005-11-18 2006-11-18 Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP06838046.8A Division EP1968627B1 (fr) 2005-11-18 2006-11-18 Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies
EP06838046.8A Division-Into EP1968627B1 (fr) 2005-11-18 2006-11-18 Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies

Publications (2)

Publication Number Publication Date
EP2815754A1 EP2815754A1 (fr) 2014-12-24
EP2815754B1 true EP2815754B1 (fr) 2016-06-08

Family

ID=38067816

Family Applications (2)

Application Number Title Priority Date Filing Date
EP06838046.8A Not-in-force EP1968627B1 (fr) 2005-11-18 2006-11-18 Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies
EP14182618.0A Not-in-force EP2815754B1 (fr) 2005-11-18 2006-11-18 Compositions pour le traitement d' infections associeés à un film biologique

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP06838046.8A Not-in-force EP1968627B1 (fr) 2005-11-18 2006-11-18 Compositions pour l'interruption et l'inhibition de la reconstitution de film biologique de plaies

Country Status (8)

Country Link
US (1) US20070116750A1 (fr)
EP (2) EP1968627B1 (fr)
JP (1) JP2009523704A (fr)
AU (1) AU2006318655B2 (fr)
CA (1) CA2630147C (fr)
ES (1) ES2526640T3 (fr)
PL (1) PL1968627T3 (fr)
WO (1) WO2007061942A2 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5548121B2 (ja) 2007-05-14 2014-07-16 リサーチ ファウンデーション オブ ステイト ユニバーシティ オブ ニューヨーク バイオフィルム中の細菌細胞における生理学的分散応答の誘導
WO2009009065A1 (fr) * 2007-07-09 2009-01-15 The Trustees Of The University Of Pennsylvania Prévention de la formation de biofilms avec de la lactoferrine
EP2173770B1 (fr) * 2007-07-10 2015-05-27 Glanbia Nutritionals (Ireland) Limited Procédé d'élimination d'endotoxines de protéines
WO2010041400A1 (fr) * 2008-10-09 2010-04-15 森永乳業株式会社 Inhibiteur de la formation de biofilm
WO2010091124A2 (fr) 2009-02-03 2010-08-12 Microbion Corporation Bismuth-thiols comme antiseptiques pour tissus épithéliaux, plaies aiguës et chroniques, biofilms bactériens et autres indications
US20130273020A1 (en) * 2010-08-30 2013-10-17 Comvita New Zealand Limited Antifungal composition
GB201207617D0 (en) * 2012-05-02 2012-06-13 Systagenix Wound Man Ip Co Bv Wound dressings
US20170027881A1 (en) * 2015-07-30 2017-02-02 Neil A. Shah Composition and related methods for treatment of pilosebaceous diseases
US20180310566A1 (en) 2017-04-29 2018-11-01 Nevada Naturals Inc. Biofilm Penetrating Compositions and Methods
WO2019227034A1 (fr) * 2018-05-25 2019-11-28 Locus Ip Company, Llc Compositions thérapeutiques permettant la cicatrisation améliorée de plaies et de cicatrices
US11541105B2 (en) 2018-06-01 2023-01-03 The Research Foundation For The State University Of New York Compositions and methods for disrupting biofilm formation and maintenance

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4783448A (en) 1983-06-07 1988-11-08 Perstorp Ab Method for cleansing an infected sore
US6291431B1 (en) 1997-12-19 2001-09-18 Panorama Research Methods and compositions for the treatment and prevention of Staphylococcal infections
JP2001181160A (ja) * 1999-12-27 2001-07-03 Morinaga Milk Ind Co Ltd 嚥下可能な口腔清浄組成物
US6716819B2 (en) * 2000-05-19 2004-04-06 University Of Iowa Research Foundation Use of xylitol to reduce ionic strength and activate endogenous antimicrobials for prevention and treatment of infections
US6399092B1 (en) 2000-12-27 2002-06-04 Healthpoint, Ltd. Anhydrous, hydrophilic absorbent wound dressing (tube) with antimicrobials or other pharmaceutically active agents
JP2002302404A (ja) * 2001-04-02 2002-10-18 Shiseido Co Ltd 抗菌防黴助剤
FR2822700B1 (fr) * 2001-04-03 2007-04-06 Frederic Dana Nouveau produit d'hygiene dentaire sous forme de nutricament unidose gelifiant d'action prolongee et compositions nouvelles adaptees en comprime ou gel semisolide
CN1578670B (zh) * 2001-08-23 2013-09-04 韦斯特盖特生物有限公司 乳清脱辅基蛋白在预防或治疗微生物或病毒感染中的用途
EP1499341A4 (fr) * 2002-04-18 2010-10-27 Univ Iowa Res Found Procede pour inhiber et traiter de films biologiques au moyen de chelateurs metalliques
DK2298338T3 (da) * 2002-09-16 2012-09-24 Agennix Inc Lactoferrin-sammensætninger og fremgangsmåder til behandling af hudsår
CA2500829A1 (fr) * 2002-10-22 2004-05-06 Nucryst Pharmaceuticals Corp. Methodes de traitement prophylactique
US20040214750A1 (en) * 2003-04-28 2004-10-28 Georgiades Izolda M. Medicaments for healing skin conditions in humans
WO2005018701A1 (fr) 2003-08-25 2005-03-03 Kane Biotech Inc. Compositions antimicrobiennes synergiques et procedes d'inhibition de la formation de biofilms
AU2004270258A1 (en) * 2003-09-09 2005-03-17 3M Innovative Properties Company Antimicrobial compositions and methods
US7144992B2 (en) * 2004-04-01 2006-12-05 Kane Biotech Inc. Synergistic antimicrobial compositions and methods for reducing biofilm formation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
EP2815754A1 (fr) 2014-12-24
EP1968627A4 (fr) 2012-04-25
ES2526640T3 (es) 2015-01-14
WO2007061942A3 (fr) 2009-04-30
CA2630147A1 (fr) 2007-05-31
AU2006318655A1 (en) 2007-05-31
EP1968627A2 (fr) 2008-09-17
PL1968627T3 (pl) 2015-04-30
JP2009523704A (ja) 2009-06-25
WO2007061942A2 (fr) 2007-05-31
US20070116750A1 (en) 2007-05-24
AU2006318655B2 (en) 2013-03-28
EP1968627B1 (fr) 2014-12-10
CA2630147C (fr) 2015-08-11

Similar Documents

Publication Publication Date Title
EP2815754B1 (fr) Compositions pour le traitement d' infections associeés à un film biologique
Vachhrajani et al. Science of wound healing and dressing materials
WO2008103673A1 (fr) Compositions pour traiter des biofilms, et procédés pour leur utilisation
KR20150113035A (ko) 표면 상처의 치료를 위한 조성물 및 방법
US8426384B2 (en) Wound-healing pharmaceutical compositions in the form of a sterile powder based on amino acids and sodium hyaluronate
Jacobsen Topical wound treatments and wound‐care products
US11975053B2 (en) Wound treatment containing collagen and a gelatin-reducing agent, and method for promoting wound healing
Issaka State-of-the-art of synthesized exosomes and NPs-based biomimetic nanoparticles for wound rehabilitation: A review
WO2019078931A1 (fr) Miel de sarrasin et pansement de cicatrisation pour plaie à base de bacitracine
WO2019040185A1 (fr) Miel de sarrasin et pansement de cicatrisation pour plaie à base de povidone iodée
Jacobsen Update on wound dressings: indications and best use
WO2017030388A1 (fr) Composition pour le traitement de lésions cutanées
Sehgal et al. Drug delivery dressings
Huang et al. Aquacel® Ag with Vaseline gauze in the management of toxic epidermal necrolysis (TEN)
US20080102106A1 (en) Wound Healing Composition Comprising Substances From Diptera Larvae
US11213564B2 (en) Buckwheat honey and bacitracin wound-healing dressing
Buote Wound Dressings
Choudhury et al. Film: A Miscellaneous Drug Delivery with its Current Application in Diabetic Wound Healing
Emadi et al. Efficacy of a novel repairing gel therapy for the management of chronic wounds: a single-center, self-controlled pilot trial
Thompson Pressure Wound Therapy Wound
KR20020087210A (ko) 상처치유 조성물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140828

AC Divisional application: reference to earlier application

Ref document number: 1968627

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

R17P Request for examination filed (corrected)

Effective date: 20150529

RBV Designated contracting states (corrected)

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20150714

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20160329

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 1968627

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 804735

Country of ref document: AT

Kind code of ref document: T

Effective date: 20160715

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602006049334

Country of ref document: DE

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 804735

Country of ref document: AT

Kind code of ref document: T

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160909

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161008

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161010

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602006049334

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20170309

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20170919

Year of fee payment: 12

Ref country code: IT

Payment date: 20170926

Year of fee payment: 12

Ref country code: FR

Payment date: 20170929

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20170919

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20171026

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20061118

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20160608

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602006049334

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20181118

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181118

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190601

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181118

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181118